Dr. Taylor-Cousar is committed to developing an academic career in clinical and translational research that contributes to the understanding of the pathophysiology and treatment of Cystic Fibrosis (CF) lung disease. Her involvement in research began prior to medical school, and has continued throughout her training. She has published manuscripts and obtained funding for projects performed during medical school, residency and fellowship. Additionally, she demonstrated an exceptional ability to bridge scientists from multiple institutions and laboratories during her fellowship project. In a short period of time after she assumed her first faculty position, Dr. Taylor-Cousar utilized funding and training from the CF Foundation to establish the infrastructure for a CF clinical research program at the University of New Mexico (UNM). At the same time, she developed her investigator-initiated protocols, for which she received internal and external funding. As faculty at National Jewish Health (NJH), Dr. Taylor-Cousar will benefit from the wealth of scientific collaborations that are available. She will receive mentorship from leaders in the field of pulmonary medicine both at NJH and Children's Hospital, and she will have access to the well-established infrastructure for clinical and translational research that is available within the CF program as well as through the Colorado Clinical and Translational Science Institute. Her mentors and the institution are committed to providing the time and support that Dr. Taylor-Cousar will need to fulfill her exceptional potential to become an independent clinical investigator. Although Dr. Taylor-Cousar gained some experience in trial oversight through her activities in the CF Therapeutics Development Network, she has identified specific training needs that will be essential for her to develop her career; these include training in laboratory techniques used to evaluate biomarkers critical to the conduct of CF clinical research, development of expertise in the design of clinical trials through formal training in statistical methods and analysis and pharmacology, establishment of a mentoring team to obtain guidance from senior investigators with experience in the design and conduct of clinical trials, and refinement of the fundamental scientific and administrative skills necessary to become a productive, independent academic clinical scientist. Her plans for fulfilling these training needs have been detailed in her career development plan and will include coursework through the Masters in Clinical Research Program, hands-on training in the laboratory, and mentorship. Dr. Taylor-Cousar's research project will focus on using a specific drug class to explore central aspects of the pathobiology of CF lung disease. The proposed therapeutic intervention will address two factors critical to the pathology that leads to the morbidity and mortality from CF: 1) Dehydrated airway surfaces resulting from sodium hyperabsorption and lack of chloride secretion, and 2) Airway damage caused by chronic lung infection and inflammation. Previously published work in CF cell lines has demonstrated that by increasing cGMP and restoring inhibition of ENaC, sodium hyperabsorption may be reversed by administration of a phosphodiesterase inhibitor (PDEi), such as sildenafil.5 Using sildenafil to restore ENaC inhibition results in normalization of organellar hyperacidification and its downstream effects, including disordered glycosylation, predisposition to adherence by Pseudomonas aeruginosa and consequent inflammation.6-7 Additionally, it has been shown in CF cell lines and animal models, that PDEi/analogues can enhance chloride secretion and/or correct surface localization of F508del CFTR.8-9 Finally, clinical evidence suggests the potential for improvement in both subjective and objective measurements of exercise tolerance in patients with severe CF lung disease and pulmonary vascular disease who are treated with sildenafil.10 The goal of this project is to translate the results from this body of work into clinical trials in patients with CF using an FDA-approved oral therapy. The Specific Aims of this project are to: 1) Establish safety and tolerability of systemic PDEi administration to subjects with CF 2) Demonstrate that pharmacokinetics of systemic PDEi administration in patients with CF are equivalent to those without CF and 3) Establish the mechanism(s) for use of systemic PDEi administration in CF lung disease by measuring outcomes before and after therapy. The results of these pilot studies will aid in establishing safety, pharmacokinetics and mechanism of action of sildenafil in the treatment of CF lung disease. Dr. Taylor-Cousar will use data from the pilot studies described in this application, and the skills and knowledge base she develops during the period of this award, to design a large, multi-center trial to determine if systemic PDEi administration will improve lung function, frequency of exacerbations and exercise tolerance in CF lung disease